Calreticulin promotes angiogenesis via activating nitric oxide signalling pathway in rheumatoid arthritis
Calreticulin promotes angiogenesis via activating nitric oxide signalling pathway in rheumatoid arthritis
复制标题
DOI：
10.1111/cei.12411
复制
发表时间：
2014-11-01
影响因子：
4.6
通讯作者：
Zheng, F.
中科院分区：
文献类型：
--
作者：
Ding, H.;Hong, C.;Zheng, F.
钙网蛋白（CRT）是一种多功能内质网蛋白，参与类风湿关节炎（RA）的发病机制。本研究旨在确定CRT是否通过激活一氧化氮（NO）信号通路参与血管生成。我们探讨了CRT在RA（包括血清、滑液和滑膜组织）中的表达情况。为探讨CRT对血管生成的作用，本研究分离培养人脐静脉内皮细胞（HUVECs）进行体外实验。我们的结果表明，显着较高浓度的CRT在血清中（5.4 +/- 2.2 ng/ml），与骨关节炎患者相比（OA，3.6 +/- 0.9 ng/ml，P < 0.05）和健康对照组（HC，3.7 +/- 0.6 ng/ml，P < 0.05）; RA的滑液中CRT（5.8 +/- 1.2 ng/ml）显著高于OA（3.7 +/- 0.3 ng/ml，P < 0.05）。高水平的CRT在滑膜中表达，主要定位于RA滑膜组织（RAST）的衬里层和亚衬里层中的炎性细胞和滑膜血管周围区域。CRT刺激后，HUVECs中一氧化氮（NO）的产生和内皮型一氧化氮合酶（eNOS）的磷酸化水平增加，而总eNOS表达无明显变化。CRT还能促进HUVECs的增殖、迁移和管腔形成，而eNOS特异性抑制剂能显著抑制CRT的促增殖、迁移和管腔形成。这些结果表明，CRT可能通过NO信号通路参与RA的血管生成，这可能为RA的治疗提供了一个潜在的治疗靶点。
Calreticulin (CRT) is a multi-functional endoplasmic reticulum protein implicated in the pathogenesis of rheumatoid arthritis (RA). The present study was undertaken to determine whether CRT was involved in angiogenesis via the activating nitric oxide (NO) signalling pathway. We explored the profile of CRT expression in RA (including serum, synovial fluid and synovial tissue). In order to investigate the role of CRT on angiogenesis, human umbilical vein endothelial cells (HUVECs) were isolated and cultured in this study for in-vitro experiments. Our results showed a significantly higher concentration of CRT in serum (5.4 +/- 2.2 ng/ml) of RA patients compared to that of osteoarthritis (OA, 3.6 +/- 0.9 ng/ml, P < 0.05) and healthy controls (HC, 3.7 +/- 0.6 ng/ml, P < 0.05); and significantly higher CRT in synovial fluid (5.8 +/- 1.2 ng/ml) of RA versus OA (3.7 +/- 0.3 ng/ml, P < 0.05). High levels of CRT are expressed in synovial membrane localized predominantly to inflammatory cells and synovial perivascular areas in both the lining and sublining layers of RA synovial tissue (RAST). Increased nitric oxide (NO) production and phosphorylation level of endothelial nitric oxide synthase (eNOS) were measured in HUVECs following CRT stimulation, while the total eNOS expression was not significantly changed. Furthermore, CRT promoted the proliferation, migration and tube formation of HUVECs, which were significantly inhibited by a specific eNOS inhibitor. These findings suggested that CRT may be involved in angiogenesis events in RA through NO signalling pathways, which may provide a potential therapeutic target in the treatment of RA.